ALBERT

Description: Background: survival of young patients with high IPI DLBCL treated with RCHOP chemotherapy needs to be improved. In this poor risk population the combination of RCHOP with new drugs is an attractive approach, along with performing an early evaluation with PET/CT after 2 to 4 cycles and change induction therapy if a complete response is not achieved. Bortezomib has been combined with RCHOP [1]. We present preliminary data of patients treated in a clinical trial comparing 6 cycles of RCHOP vs 6 cycles of BRCAP, a modified RCHOP regimen changing vincristine by bortezomib at a dose of 1.3 mg/m2 sc days 1, 8, and 15 of every 21 days cycle (NCT01848132). Methods: patients younger than 70 yrs diagnosed of DLBCL with aIPI 2-3 or aIPI 1 with elevated beta2microglobulin were eligible. The main objective was to evaluate the proportion of patients who survives free of event at 2 years. Central pathology review was performed in all cases, and samples were classified as GC vs non-GC subtypes by IHC (Hans algorithm). PET/CTs were performed at diagnosis, after 2, 4 and 6 cycles (PET2, PET4 , and PET6), and were reviewed by at least 3 experts of a central panel at real time. Response was analyzed following the visual method with the Deauville scale, and for PET2 and PET4 the semiquantitative method was used. Patients with persistent disease after 4 cycles were considered a failure of therapy and were dropped out from the trial. Results: data from the first 76 patients were analyzed. Diagnosis of DLBCL was confirmed in all except 3 pts, 36 pts were treated in the experimental arm and 37 in the control arm. Median age was 58.2 yo (range 23-70), 37 (50.7%) were males. Characteristics at diagnosis were: non-GC subtype 18/46 (39.1%), C-myc expression 35/43 (81.4%), bcl2 expression 43/49 (87.7%), double expression cmyc/bcl2 30/42 (71%), stage III-IV 64 (87.6%), ≥2 extranodal locations 27 (42.2%), ECOG 2-3 24 (33%), elevated LDH 43 (62.3%), elevated beta 2 microglobulin 47 (75.8%), aIPI 2: 42 (57.5%), aIPI 3: 21 (28.8%). Among 160 cycles of BRCAP chemotherapy, 5 (3.1%) on day 8, and 22 (13.7%) on day 15, were given without bortezomib due to a neutrophil count below 0.5 /L. The most common toxicities are shown in table 1 without significant differences between both arms. Twenty-one (32.8%) out of 64 patients had a positive PET2. Fifteen (26.8%) out of 56 patients who have finished the 4 cycles had a positive PET4 according to central review and were withdrawn of the trial. Table 1. Episodes of treatment-related adverse events Control arm: RCHOP n=166 Experimental arm: BRCAP n=160 Any grade Grade 3-4 Any grade Grade 3-4 Anemia 6 0 22 9 ( 5.6%) Neutropenia 31 26 (15.6%) 47 37 (23.1%) Thrombocytopenia 9 4 ( 2.4%) 16 5 ( 3.1%) Febrile neutropenia - 6 ( 3.6%) - 10 ( 6.2%) Fever 8 1 ( 0.6%) 8 0 Infection 4 1 ( 0.6%) 7 1 ( 0.6%) Nausea/vomiting 12 0 19 0 Peripheral neuropathy 7 1 ( 0.6%) 7 1 ( 0.6%) Diarrhea 4 0 8 0 Constipation 7 0 4 0 Hepatotoxicity 6 0 6 0 Conclusions: BRCAP regimen with bortezomib sc d1, 8, and 15 is feasible. Its main toxicity is hematological, and some patients cannot receive some doses of bortezomib due to neutropenia. Grade 3-4 non-hematological toxicity is rare, including peripheral neuropathy, and do not differ from RCHOP toxicity. 1.Ruan J et al, JCO 2011;29:690-7 Disclosures Sancho: CELLTRION, Inc.: Research Funding. Lopez-Guillermo:Roche, Celgene, Mundipharma, Gilead, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background and objectives Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients. The aim of this study is to determine the ability of the Vivia’s novel ex vivo drug sensitivity platform Exvitech analyzing leukemic cell death to predict the CR rates after induction chemotherapy with cytarabine (Ara-C) and idarubicin (Ida) in 1st line AML. Patients and Methods This non-interventional and prospective study included samples from adult patients over 18 years of age diagnosed with de novo AML in Spanish centers from the PETHEMA group. Marrow samples were collected at diagnosis, sent to the Vivia laboratories, and incubated for 48 hours in whole samples in well plates containing Ara-C, Ida, or the combination Ara-C+Ida, each at 8 different concentrations to calculate dose responses. Annexin V-FITC was used to quantify the drug-induced apoptosis. Pharmacological responses are calculated using pharmacokinetic population models. Induction response was assessed according to the Cheson criteria (2003). Patients attaining a CR/CRi were classified as responders. The remaining patients were considered as resistant. Patients dying during induction response assessment were non-evaluable. The correlation was modeled using a generalized additive model with a logit link and a binomial distribution for residuals. Kernel density estimates were then used to plot empirical probability density functions for both groups. Their separation was quantified as the area under the ROC curve and a cut point was selected using the Youden’s criteria to optimize the classification probabilities (sensitivity, specificity). 95% confidence intervals for sampling errors were calculated for all these quantifiers. Results 125 patient samples were used to calculate the dose response curves for Ara-C alone, Ida alone, and the synergism of the Ara-C plus Ida combination. For clinical correlation we used 64 patients with a median age of 55 years (range 31 to 72). Dose responses for Ara-C alone are shown in Figure 1.A; note that for many samples there is a significant number (〉20%) of resistant cells to Ara-C (bracket). This is a strong clinical predictor of resistance because in the patient the drug will never be present at these high doses for 48 h. The second variable that is a good predictor of response is the synergism between these 2 drugs. The generalized additive model identified an algebraic combination of these 2 variables that yielded the best marker to separate both groups of patients. The probability density functions had minimal overlap. The area under the corresponding ROC curve was 0.965 (0.928, 1.000), and the classification probabilities for the optimal cut point (set at 0.414 for the marker), expressed as percentages, were 85% (62.1% to 96.8%) and 86.4% (72.6% to 94.8%) for sensitivity and specificity, respectively. Results are shown in Figure 1.B; Forty-four patients (68.8%) achieved CR after Ida+Ara-C, and the remaining 20 (31.3%) were resistant. Correlations of the PM test are shown in Figure 1.B. Seventeen of the 20 (85%) patients who fail to achieve CR were predicted as resistance in the ex vivo test. Thirty-eight of the 44 patients (86.4%) who achieved CR showed good ex vivo sensitivity to Ida+Ara-C predicting for CR. When the ex vivo test predicted a patient as sensitive it was correct in 38/39 cases (93%), and when it predicted resistant it was correct 17/23 cases (74%). Overall, 45 patients (86%) had an accurate prediction of their response to treatment. Conclusions This study shows that this novel ex vivo pharmacological profile test is able to predict the clinical response to Ida+Ara-C induction. We are increasing the number of patients in this ongoing study, and we are planning a PM Test-adapted Clinical Trial. Disclosures: Martínez: Vivia Biotech: Employment. Ortega:Vivia Biotech: Employment. Primo:Vivia Biotech: Employment. Hernandez-Campo:Vivia Biotech: Employment. Rojas:Vivia Biotech: Employment. Bennett:Vivia Biotech: Employment. Liebana:Vivia Biotech: Employment. Lopez:Vivia Biotech: Employment. Ballesteros:Vivia Biotech: Equity Ownership.

Description: Introduction: Relapses after front-line therapy for Burkitt lymphoma/leukemia (BL) are unfrequent, and there is scarce information about the best rescue strategy for these patients. The objective of this study was to evaluate the incidence of relapse, salvage treatment and prognosis after relapse in patients with BL treated with two consecutive Spanish protocols. Patients and methods: Retrospective study of patients diagnosed with BL in 40 Spanish hospitals betwen January 1997 and October 2014 treated with first line chemotherapy according to protocols PETHEMA LAL-3/97 (specific chemotherapy without rituximab) and BURKIMAB (rituximab plus specific chemotherapy). The demographic, clinical and biological characteristics were collected at the time of diagnosis and at relapse, as well as the salvage treatment and outcomes. Results: 233 patients were diagnosed with Burkitt lymphoma (n=150) or leukemia (n=83) and received first-line therapy according to PETHEMA LAL-3/97 (n=53) and BURKIMAB (n=180) protocols. Baseline characteristics at diagnosis are described in Table 1. A total of 26 patients relapsed, 11 (28%) treated with PETHEMA LAL-3/97 protocol and 15 (10%) with BURKIMAB protocol (p=0.009). The cumulative incidence of relapse at 10 years was 27% (95% CI, 12%-42%) in PETHEMA LAL-3/97 protocol vs.16% (95% CI, 4%-28%) in BURKIMAB protocol (p= 0.013) (Figure 1). Time to relapse was shorter in PETHEMA LAL-3/97 protocol (median of 3.7 months) vs. BURKIMAB protocol (6.3 months), but it was not significant (p=0.506). No differences were observed in relapse incidence between Burkitt leukemia and Burkitt lymphoma in PETHEMA LAL-3/97 protocol (6/31 vs. 5/22, p=1) and BURKIMAB protocol (7/41 vs. 8/107, p=0.124). Out of 15 patients in whom rescue treatment strategy was evaluable, 12 received chemotherapy with high-dose methotrexate and/or cytarabine (4 of the them followed response, CR in 2, followed by SCT in the 2 patients achieving PR [autologous in one and allogeneic SCT in the other]), and the remaining 3 patients received DA-EPOCH-R (n=1, achieving CR), R-ICE (n=1, no response) and paliative care (n=1). At the time of the analysis, only 3 patients are alive. Median overall survival after relapse was 3 months (95% CI, 0.9-5.1) for PETHEMA LAL-3/97 relapsed group and 3.6 months (95% CI, 0.1-7.1) for BURKIMAB relapsed patients group. Conclusions: Patients with Burkitt leukemia/lymphoma treated with specific immunochemotherapy have lower probability of relapse compared with those treated with specific chemotherapy without rituximab. In our series, the most frequent regimens administered for the treatment of relapsed patients were based in high-dose methotrexate and/or cytarabine. The prognosis of relapsed Burkitt leukemia/lymphoma is poor, independently of the type of rescue therapy. Supported by grants RD12/0036/0029 (RTICC, FEDER), Instituto Carlos III, Spain. Disclosures No relevant conflicts of interest to declare.

Description: Background: Survival of DLBCL patients with high IPI treated with RCHOP immunochemotherapy is poor. In this population, the combination of RCHOP with new drugs is an attractive approach, along with performing an evaluation with PET/CT after 2 to 4 cycles to change the therapy if an early complete response is not achieved. Methods : We performed a clinical trial comparing 6 cycles of RCHOP vs 6 cycles of BRCAP, a modified RCHOP regimen changing vincristine by bortezomib 1.3 mg/m2 sc days 1, 8, and 15 of a 21-day cycle. Pre-phase therapy was permitted for patients who could not wait the results of the screening procedures to start therapy due to the aggressiveness of the disease. (ClinicalTrials.gov Identifier: NCT01848132). Patients younger than 71 yrs diagnosed with DLBCL and an age-adjusted IPI (aaIPI) 2-3 or aaIPI 1 with increased beta2microglobulin were eligible. The primary endpoint was the proportion of patients who survives free of event at 2 years. Centralized anatomopathology review was performed in all cases; samples were classified as germinal center B-cell-like (GCB) vs non-GCB subtypes by immunohistochemistry according to the Hans algorithm. PET/CTs were performed baseline, after 2, 4 and 6 cycles (PET2, PET4, and PET6), and were reviewed at real time by at least 3 experts of a central panel. Response at the end of therapy was analyzed following the visual method with the Deauville scale, and response after PET2 and PET4 was evaluated using the semiquantitative method. Persistent disease at PET4 was considered as failure of therapy and these patients were removed from trial treatment. EFS was calculated from diagnosis until event defined as death from any cause, relapse, progression or need of salvage therapy (defined as PET4 or PET6 positive). Overall survival (OS) was calculated from diagnosis until death for any cause. We present here a preliminary analysis of results. Results: One hundred and twenty-one patients were included; data on 113 are presented (diagnosis not confirmed in 6, data missing in 2). Median age was 57.1 yrs (range 23-70), 57 (50.4%) were males. Characteristics at diagnosis were: non-GCB subtype 32/87 (36.8%), immunohistochemical co-expression of myc/bcl2 56/82 (77.8%), stage III-IV 107 (94.7%), ≥2 extranodal locations 55/76 (72.5%), ECOG 2-3 36 (32.1%), increased LDH 88 (77.9%), increased beta 2 microglobulin 73 (64.6%), aaIPI 3: 32 (28.3%). No differences were found between treatment arms. Fifty-five patients were treated in the experimental arm (EA) and 58 in the control arm (CA). Twenty-eight (28.3%) out of 99 patients required of pre-phase treatment. The mean relative dose intensity for bortezomib was 88.3%. Data about the most frequent toxicity are shown in table 1. Twenty-nine (30.2%) out of 96 patients who have finished 4 cycles had a positive PET4 according to central review and were withdrawn to receive salvage therapy. Complete remission (CR) at the end of therapy (PET4-/PET6-) was observed in 44 (45.8%) patients. After a median follow-up of 9 months, estimated 12-mo EFS was 36.6%, and 12-mo OS was 82.9% in the whole series. Data of the subgroup analysis according the immunohistochemistry subtypes by Hans algorithm are show in table 2. Conclusions: In the present preliminary analysis, no significant differences were found between RCHOP and BRCAP in terms of CR and EFS in this very high-risk population of young DLBCL patients. However, in the subgroup analysis of patients with non-GCB disease, we found a significantly better CR rate in patients treated with BRCAP. A longer follow-up is needed to evaluate the real impact of this therapy on survival. Disclosures González-Barca: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Martín:Sevier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Sancho:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. López-Jiménez:Abbvie: Membership on an entity's Board of Directors or advisory committees; Velgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; MundiPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. López-Guillermo:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; MundiPharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ramírez:Bristol-Myers-Squibb: Honoraria; Novartis: Honoraria; Roche: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Conde:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees.

Description: Background: The 2016 reviewed classification of the World Health Organisation (WHO) defines a group of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) including the chronic myelomonocytic leukemia (CMML), the myelodyplastic syndrome with ring sideroblasts and thrombocytosis (MDS-RS-T) and the MDS/MPN unclassifiable (MDS/MPN-U). The presence of typical clinical characteristics of MDS and MPN hinders the diagnosis and the prognosis of MDS/MPN-U. Aim: The objective of this study was to compare the clinical characteristics and the prognosis of a series of patients with MDS/MPN such as CMML, MDS-RS-T and MDS/NPM-U from the Spanish registry of MDS. Method: We analized 107 patients diagnosed with MDS/MPN (MDS-RS-T, MDS/NPM-U and CMML) according to the 2016 WHO classification. A comparison of the clinical characteristics, overall survival (OS) and cumulative incidence of progression (CIP) was performed. Results: Median (range) age was 74 (23-93) years and 68/107 (64%) were males. The number of patients in each group was: MDS-RS-T (n=45), MDS/MPN-U (n=29) and CMML (n=33). The main clinical characteristics of the three groups are described in Table 1. There were significant statistical differences in hemoglobin and lactate dehydrogenase levels and leukocyte, monocyte and platelet counts between the three groups. With a median (range) of follow-up of 3.1 (0.3-19.3), 3.7(0.7-10.4) and 4 (1.8-8.5) years for MDS-RS-T, MDS/MPN-U, and CMML, respectively, the OS (95%CI) at 5 years was significantly better in patients with MDS-RS-T (61% [42%; 80%]) compared to MDS/MPN-U and CMML patients (21% [1%; 41%] and 19% [3%; 35%], p=0.002) (Figure 1). The CIP (95%CI) at 5 years between the three groups was significantly different: MDS/MPN-U and CMML (40% [18%; 61%] and 32% (14%-52%, respectively) vs. MDS/RS-T 8% [0.4%; 30%]) (p=0.005) (Figure 2). Conclusions: 1) In this series of patients with MDS/MPN (MDS-RS-T, MDS/MPN-U and CMML) according to the 2016 WHO classification clinical characteristics were similar except for hemoglobin and lactate dehydrogenase levels and leukocyte, monocyte and platelet counts. 2) Patients with MDS-RS-T had longer OS and less CIP than those with MDS/MPN-U and CMML; 3) The prognosis of MDS/MPN-U and CMML were similar. Supported by grants from: AGAUR 9015-470120/2015, 2017-SGR288 (GRC), CERCA Program from Generalitat de Catalunya, and "La Caixa" Foundation. Disclosures No relevant conflicts of interest to declare.

Description: Background and objective. Idelalisib is an oral inhibitor of the p110δ isoform of PI3K (phosphoinositide 3-kinase) approved in Europe and USA as monotherapy in relapsed/refractory follicular lymphoma (FL) after 2 previous lines of therapy based on a phase 2 study (Gopal et al, N Eng J Med 2014). However, there are scarce data on the use of idelalisib in clinical practice (Eyre et al, Br J Haematol 2017). The objective of this study was to analyze the efficacy and toxicity of idelalisib in relapsed/refractory FL patients in clinical practice in Spanish hospitals of GELTAMO group (GELT-IDE-2018-02 Study). Patients and Methods. Retrospective study of relapsed/refractory FL patients treated with idelalisib as salvage therapy in clinical practice. Demographic and clinical and biological variables were analyzed at FL diagnosis and at the time of idelalisib therapy, as well as its efficacy and toxicity. Results. A total of 43 patients from 20 hospitals were included. At time of idelalisib therapy, median age was 63 years (range 44-83), number of previous lines of therapy was 3 (2-7), 42% (n=18) were refractory to last previous treatment and 42% (n=18) had received an autologous stem cell transplantation (SCT); 56% (n=24) had progressed in the first 24 months after FL diagnosis (POD24). Median duration of treatment with idelalisib at time of analysis was 8.1 months (1.1-37.4) and 28/43 patients (65%) discontinued therapy, 13 due to progression, 12 due to adverse events (AE) and 3 due to physician's decision. Overall response rate (ORR) was 73% (32% CR) and median PFS 14.6 months (95% CI 0-32.2), with a trend to be higher in non-POD24 group (median PFS of 9.4 months [95% CI 1.7-16.9] in POD24 vs. 27 months [95% CI NA] in non-PO24 patients, p=0.082); median duration of response to idelalisib was 25.1 months (95% CI 13.1-37.6). Median overall survival (OS) was not reached at the time of analysis, with a 2-year OS of 74% (95% CI 58%-90%) (Figure). In 4 patients, an allogeneic SCT was performed after idelalisib. A total of 86% (n=37) of patients showed any AE, being in 56% (n=24) of grade ≥3 AE. Toxicities of grade ≥3 more frequent were: neutropenia (23% of patients), diarrhea (23%), infections (23%: pneumonia in 4 patients, CMV infection in 2, febrile neutropenia in 1 and other infections in 3 [1 of them died due to Aspergillus infection]), and increased transaminases (9%). Conclusions. In this series of patients with relapsed/refractory FL, several previous lines of therapies and factors associated with poor prognosis, the treatment with idelalisib was associated with efficacy and toxicity similar to published studies. These results support the use of idelalisib as an option for FL patients with multiple or poor risk relapses. Financial support: Gilead Figure. Progression-free survival (PFS) and overall survival (OS) for patients with follicular lymphoma treated with idelalisib. Figure Disclosures Sancho: SERVIER: Honoraria; SANOFI: Honoraria; Novartis: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CELLTRION: Consultancy; Kern-Pharma: Honoraria; Sandoz: Consultancy. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ramirez Payer:GILEAD SCIENCES: Research Funding. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Martín:Kiowa Kirin: Consultancy; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; iQone: Consultancy; Teva: Research Funding; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Expenses; Servier: Honoraria, Other: Travel Expenses. Armando:Roche: Consultancy, Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.